PHYSIOLOGICAL MODELING OF FORMULATED AND CRYSTALLINE 3,3′-DIINDOLYLMETHANE PHARMACOKINETICS FOLLOWING ORAL ADMINISTRATION IN MICE
- 20 May 2004
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 32 (6), 632-638
- https://doi.org/10.1124/dmd.32.6.632
Abstract
3,3′-Diindolylmethane (DIM) is a naturally occurring indole, which is currently under investigation as a potential chemopreventive agent. The concentrations of DIM in plasma, liver, kidney, lung, heart, and brain tissues were determined following oral administration of two different formulations to mice (250 mg/kg). Mice were sacrificed periodically from 0 to 24 h after administration of either a crystalline or an absorption-enhanced formulation (Bio-Response-DIM; Indolplex) of DIM, and plasma and tissue concentrations were determined by high-performance liquid chromatography (UV detection, 280 nm). A physiologically based pharmacokinetic (PBPK) model was developed to characterize the pharmacokinetic properties of the two different formulations. The final model included parameters reflecting linear first-order absorption, systemic clearance, and distributional clearance in the remainder compartment, which were considered independent of formulation. All pharmacokinetic profiles from the two formulations were fitted simultaneously to estimate unknown model parameters. Plasma and tissue concentration-time profiles exhibited a rapid rise to peak values at 0.5 to 1 h, followed by a polyexponential decline with an extended terminal phase. These profiles were well described by the final model and unknown parameters were estimated with relatively low coefficients of variation. Relative drug exposure and absorption parameters suggest that BioResponse-DIM exhibited approximately 50% higher bioavailability than the crystalline formulation. Clearance of DIM was estimated as 7.18 ml/h. This is the first study to characterize the pharmacokinetics of DIM in mice, and the established PBPK model should prove useful in the design and analysis of future preclinical studies aimed at evaluating the in vivo pharmacological effects of DIM.Keywords
This publication has 25 references indexed in Scilit:
- Indole-3-Carbinol and Diindolylmethane Induce Apoptosis of Human Cervical Cancer Cells and in Murine HPV16-Transgenic Preneoplastic Cervical EpitheliumJournal of Nutrition, 2001
- Placebo-Controlled Trial of Indole-3-Carbinol in the Treatment of CINGynecologic Oncology, 2000
- Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethaneCarcinogenesis: Integrative Cancer Research, 1998
- Physiological Parameter Values for Physiologically Based Pharmacokinetic ModelsToxicology and Industrial Health, 1997
- Quantitative structure-pharmacokinetics relationships: I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat.Journal of Pharmacokinetics and Biopharmaceutics, 1997
- 3,3′-Diindolylmethane Induces Apoptosis in Human Cancer CellsBiochemical and Biophysical Research Communications, 1996
- Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in miceCarcinogenesis: Integrative Cancer Research, 1991
- Structure elucidation of acid reaction products of indole-3-carbinol: Detection in vivo and enzyme induction in vitroChemico-Biological Interactions, 1991
- In vivo disposition of the natural anti-carcinogen indole-3-carbinol after PO administration to rainbow troutFood and Chemical Toxicology, 1989
- Structure—activity relationships of dietary indoles: A proposed mechanism of action as modifiers of xenobiotic metabolismJournal of Toxicology and Environmental Health, 1987